The objective of this research is to understand the mechanisms through which sex hormones regulate the innate immune system in the female reproductive tract (FRT). Our overall hypothesis is that sex hormones regulate innate immune cell (epithelial, macrophage/dendritic cells, neutrophils and NK cells) defenses in the FRT which maintain a baseline of protection, in anticipation of probable pathogen entry, and respond to potential pathogens and pathogen-associated molecular patterns (PAMPs) by (1) secreting antimicrobials, (2) producing cytokines and chemokines that recruit and activate immune cells and (3) alerting the adaptive immune system to invaders. Throughout this proposal we plan to test the hypothesis that estradiol (E2) and progesterone (P) regulate innate immune responses (antimicrobials, cytokines, chemokines) and provide linkage to adaptive immunity that can lead to the protection of the reproductive tract against pathogens. The aims of the current research project are to answer the following questions: 1. Which antimicrobials, cytokines and chemokines are in FRT secretions during the estrous cycle and under hormonal control? 2. Does Toll-like receptor (TLR) expression vary with stage of the estrous cycle and is expression regulated by E2 and P? 3. Are innate immune responses to PAMPs regulated by E2 and P and if so, is regulation direct or mediated through stromal fibroblasts? 4. Which fibroblast growth factors mediate E2 and P control of innate immunity? 5. How do E2 and P influence antigen presentation in the uterus and vagina? We plan to investigate these questions using our in vivo and in vitro mouse model, since both are known to be responsive to sex hormones. Overall, these studies will increase our limited understanding of the role of sex hormones in regulating immune protection and should provide the basis of knowledge essential for understanding the role of hormones in the prevention and management of sexually transmitted diseases including the heterosexual transmission of HIV-1.